ABSTRACT Permanent disabilities following central nervous system (CNS) injuries result from the failure of injured axons to regenerate and re-build functional connections. The poor intrinsic regenerative capacity of adult CNS neurons is a major contributor to the regeneration failure and remains a major problem in neurobiology as well as an unmet medical need. In patients with glaucoma, the axon of retinal ganglion cells? (RGC) projecting into the optic nerve are injured, leading to RGCs death and loss of vision. Some treatment strategies can delay progression of the disease, but vision lost from the disease cannot be restored. Using adult mouse peripheral sensory neurons, which can switch to a robust axon regeneration state upon injury, my laboratory has discovered that injury elicits epigenetic changes that promote axon regeneration. Acetylation of the histone tail, which regulates chromatin dynamics and transcriptional activity, promotes expression of regeneration-associated genes (RAGs) and axon regeneration. We demonstrated that histone deacetylase 5 (HDAC5) and HDAC3 are involved in peripheral axon regeneration. Whereas neurons in the adult peripheral nervous system alter their epigenetic landscape to permit axon regeneration, RGCs may not be able to perform this task. Indeed, HDAC3 was shown to accumulate in the nucleus of injured RGCs, where it suppresses gene expression and promotes RGCs death after optic nerve injury. Consistently, inhibiting HDAC activity was shown to ameliorate RGCs survival and axon regeneration. Our data indicate that expression in RGCs of an HDAC5 mutant (with increased interaction with HDAC3) promotes axon regeneration after optic nerve injury. HDAC5 can regulate transcription by scaffolding the HDAC3 to a specific set of transcriptional targets, and we found that this HDAC5 mutant suppresses the level of SOCS3, an important negative regulator of axon regeneration. Together, these results strongly imply that the epigenetic landscape of RGCs represents a barrier to axon growth and survival after optic nerve damage and that modulating the chromatin can change RGCs? response to injury. We propose here to identify novel epigenetic modifiers that stimulate RGCs survival and regenerative capacity. These experiments may offer novel therapeutic avenues towards treatment of patients with glaucoma or other types of optic neuropathies.